Exclusion of the α2 subunit of platelet-activating factor acetylhydrolase 1b (PAFAH1B2) as a prothrombotic gene in a protein C-deficient kindred and population-based case-control sample

Summary Protein C deficiency increases the risk of venous thromboembolic disease among members of KindredVermont II, but fails to fully account for the inheritance pattern. A genome scan of the pedigree supported the presence of a prothrombotic gene on chromosome 11q23 (107–119Mb, nominal P<0.0001), with weaker support on chromosomes 10p12 (11–25Mb, P<0.0003) and 18p11.2-q11 (12–24Mb, P<0.0007).The 11q23 region contains the α2 subunit (gene name PAFAH1B2) of platelet-activating factor acetylhydrolase 1b, a candidate prothrombotic gene. Re-sequencing of the PAFAH1B2 regulatory region in 137 pedigree members, including 25 thrombosis cases, revealed 12 variants; eight were present in only 0–2 affected individuals; the other four assorted into three haplotypes and included three variants predicted to destroy transcription factor-binding sites. More extensive re-sequencing of the PAFAH1B2 gene in 11 affected and five unaffected pedigree members revealed an additional 13 variants that assorted into the same three haplotypes. We rejected as thrombosis risk factors each of the three presumed destructive variants as well as each of the three haplotypes. We also rejected (odds ratio=1.31 CI: 0.91–1.88) one of the three variants in 469 cases and 472 controls from the Leiden Thrombophilia Study (LETS). Therefore, PAFAH1B2 is not the gene responsible for the linkage evidence on chromosome 11q23.